Mammalian cells transformed by different human adenoviruses (Ad) differ markedly in tumorigenicity in immunocompetent hosts. Cells transformed by Ad types 2 or 5 are nontumorigenic, whereas cells transformed by Ad12 are highly tumorigenic. A major factor determining these differences in tumorigenicity appears to be the susceptibility of Ad transformed cells to destruction by host natural killer (NK) cells. Ad2/5 transformed cells are lysed by NK cells and are rejected by animals with competent NK cell responses, while AD12 transformed cells are NK resistant. The objective of these studies is to pursue the observation that expression of a single Ad2/5 oncogene-E1A-actively induces cellular susceptibility to NK cell mediated lysis (cytolytic susceptibility). The goals of this project are to identify the E1A oncogene subregions that control induction of the cytolytic susceptible phenotype, to study the mechanisms by which E1A induces this phenotype, and to further test the hypothesis that the host NK cell response is sufficient to reject E1A expressing tumor cells. The subregions of the Ad2/5 E1A oncogene whose expression is required for induction of cytolytic susceptibility will be mapped by mutational analysis. The hypothesis that E1A genetic domains involved in activation of cellular gene transcription are required for induction of cytolytic susceptibility will be tested by asking whether the E1A regions required for induction of cytolytic susceptibility and for cellular gene transactivation are identical. Hamster and nude rat models in which E1A oncogene expression determines tumor cell rejection in an NK cell dependent manner will be used to test the relevance of E1A oncogene mutations for determining neoplastic cell tumor inducing capacity, to study NK ontogeny, and to define NK involvement in rejection of metastatic, E1A oncogene expressing tumor cells. E1A oncogene mutations will be used to initiate studies of cellular mechanisms by which E1A induced cytolytic susceptibility is mediated. The observation that E1A expression induces susceptibility of transformed cells to lysis by TNF alpha produced by NK cells will be pursued by asking whether E1A activation of cellular nuclease activity is involved in sensitizing cells to TNF induced DNA degradation. In addition to its effects on primary transformants, E1A oncogene expression can also eliminate the tumorigenicity of established, spontaneously transformed tumor cells. This observation suggests that all cells, even highly virulent neoplastic cells, contain a latent cytolytic susceptibility pathway. The use of the E1A oncogene to define this pathway and the triggering mechanisms that activate it in neoplastic cells could provide the basis for new approaches to immunotherapy that would complement efforts to modulate cellular immunity as a host defense against neoplasia.